Chloroquine and sulfadoxine-pyrimethamine (SP) remain the first line antimalarial drugs in most sub-Saharan African countries. Plasmodium falciparum resistance to chloroquine is high in all but a few African countries, but most still use chloroquine as the first line. SP resistance has developed where this drug has been introduced, with high rates of resistance reported at some sites. Prompt and effective treatment remains the primary tool for reducing malaria morbidity and mortality, and resistance, especially to chloroquine, is linked with high rates of hospitalizations and deaths. Newer and more effective treatments for malaria are in the pipeline. High hopes are pinned on combination therapies, which are intended to deter the development of resistance. This proposal follows a major unexpected finding we made in a closely related research project in Malawi: chloroquine-sensitive falciparum malaria has reemerged and now predominates following cessation of chloroquine use in Malawi in 1993. We propose to test the efficacy of chloroquine alone and in combination with other drugs that may prevent the reemergence of chloroquine resistance. If preliminary studies suggesting that chloroquine may again be effective are borne out, chloroquine may also protect against development of resistance to new drugs. We will conduct a longitudinal clinical efficacy trial of chloroquine monotherapy and chloroquine plus SP, chlorproguanil-dapsone, and artesunate, all compared to SP, the current standard therapy in Malawi. This study design, which we and others pioneered in Malawi, permits more comprehensive assessment of antimalarial drug efficacy by measuring not only short-term treatment outcomes but the number of recurrent treatment episodes seen over time. Efficacy and prevention of resistance will be compared using measures of clinical and parasitological treatment outcomes as well as molecular markers for resistance. These studies have been designed with input from malaria control policymakers in Malawi and are expected to provide information that will directly influence treatment recommendations in that country. Results of the proposed studies will also inform malaria treatment policies in other countries where chloroquine is still used or has recently been discontinued. [unreadable] [unreadable]